Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

One-Year Recovery Among Survivors of Prolonged Severe COVID-19: A National Multicenter Cohort.

OBJECTIVES: Understanding the long-term effects of severe COVID-19 illness on survivors is essential for effective pandemic recovery planning. Therefore, we investigated impairments among hospitalized adults discharged to long-term acute care hospitals (LTACHs) for prolonged severe COVID-19 illness who survived 1 year. DESIGN: The Recovery After Transfer to an LTACH for COVID-19 (RAFT COVID) study was a national, multicenter, prospective longitudinal cohort study. SETTING AND PATIENTS: We included hospitalized English-speaking adults transferred to one of nine LTACHs in the United States between March 2020 and February 2021 and completed a survey. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Validated instruments for impairments and free response questions about recovering. Among 282 potentially eligible participants who provided permission to be contacted, 156 (55.3%) participated (median age, 65; 38.5% female; 61.3% in good prior health; median length of stay of 57 d; 77% mechanically ventilated for a median of 26 d; 42% had a tracheostomy). Approximately two-thirds (64%) had a persistent impairment, including physical (57%), respiratory (49%; 19% on supplemental oxygen), psychiatric (24%), and cognitive impairments (15%). Nearly half (47%) had two or more impairment types. Participants also experienced persistent debility from hospital-acquired complications, including mononeuropathies and pressure ulcers. Participants described protracted recovery, attributing improvements to exercise/rehabilitation, support, and time. While considered life-altering with 78.7% not returning to their usual health, participants expressed gratitude for recovering; 99% returned home and 60% of previously employed individuals returned to work. CONCLUSIONS: Nearly two-thirds of survivors of among the most prolonged severe COVID-19 illness had persistent impairments at 1 year that resembled post-intensive care syndrome after critical illness plus debility from hospital-acquired complications.

Patterns of peripartum depression and anxiety during the pre-vaccine COVID-19 pandemic.

BACKGROUND: Pregnant people are vulnerable to new or worsening mental health conditions. This study aims to describe prevalence and course of depression and anxiety symptoms in pregnancy during the pre-vaccine COVID-19 pandemic. METHODS: This is a prospective cohort study of pregnant individuals with known or suspected COVID-19. Participants completed Edinburgh Postnatal Depression Scale (EPDS) and Generalized-Anxiety Disorder-7 (GAD-7) questionnaires, screening tools for depression and anxiety, at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum. Prevalence of elevated depressive and anxiety symptoms at each visit was described. Univariable logistic regression analysis was used to determine the association between demographic and clinical factors and those with elevated depression or anxiety symptoms. RESULTS: 317 participants were included. The prevalence of elevated antepartum depression symptoms was 14.6%, 10.3%, and 20.6% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. The rate of elevated anxiety symptoms was 15.1%, 10.0%, and 17.3% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. A prior history of depression and/or anxiety (p's < 0.03), as well as higher EPDS and GAD-7 scores at enrollment (p's < 0.04) associated with elevated depression and anxiety symptoms throughout pregnancy and the postpartum period. Quarantining during pregnancy was associated with elevated anxiety symptoms at 34weeks gestational age in univariate (P = 0.027) analyses. COVID-19 diagnosis and hospitalization were not associated with elevated depression or anxiety symptoms. CONCLUSIONS: Elevated depression and anxiety symptoms were prevalent throughout pregnancy and the postpartum period, particularly in those with prior depression and/or anxiety and who quarantined. Strategies that target social isolation may mitigate potential adverse consequences for pregnant people, and continued vigilance in recognition of depression and anxiety in pregnancy should be considered.

Association of Race and Ethnicity With Postoperative Gabapentinoid and Opioid Prescribing Trends for Older Adults.

BACKGROUND: Disparities in opioid prescribing by race/ethnicity have been described in many healthcare settings, with White patients being more likely to receive an opioid prescription than other races studied. As surgeons increase prescribing of nonopioid medications in response to the opioid epidemic, it is unknown whether postoperative prescribing disparities also exist for these medications, specifically gabapentinoids. METHODS: We conducted a retrospective cohort study using a 20% Medicare sample for 2013-2018. We included patients ≥66 years without prior gabapentinoid use who underwent one of 14 common surgical procedures. The primary outcome was the proportion of patients prescribed gabapentinoids at discharge among racial and ethnic groups. Secondary outcomes were days' supply of gabapentinoids, opioid prescribing at discharge, and oral morphine equivalent (OME) of opioid prescriptions. Trends over time were constructed by analyzing proportion of postoperative prescribing of gabapentinoids and opioids for each year. For trends by year by racial/ethnic groups, we ran a multivariable logistic regression with an interaction term of procedure year and racial/ethnic group. RESULTS: Of the 494,922 patients in the cohort (54% female, 86% White, 5% Black, 5% Hispanic, mean age 73.7 years), 3.7% received a new gabapentinoid prescription. Gabapentinoid prescribing increased over time for all groups and did not differ significantly among groups (P = 0.13). Opioid prescribing also increased, with higher proportion of prescribing to White patients than to Black and Hispanic patients in every year except 2014. CONCLUSIONS: We found no significant prescribing variation of gabapentinoids in the postoperative period between racial/ethnic groups. Importantly, we found that despite national attention to disparities in opioid prescribing, variation continues to persist in postoperative opioid prescribing, with a higher proportion of White patients being prescribed opioids, a difference that persisted over time.

Which older adults are at highest risk of prescribing cascades? A national study of the gabapentinoid-loop diuretic cascade.

BACKGROUND: Prescribing cascades are important contributors to polypharmacy. Little is known about which older adults are at highest risk of experiencing prescribing cascades. We explored which older veterans are at highest risk of the gabapentinoid (including gabapentin and pregabalin)-loop diuretic (LD) cascade, given the dramatic increase in gabapentinoid prescribing in recent years. METHODS: Using Veterans Affairs and Medicare claims data (2010-2019), we performed a prescription sequence symmetry analysis (PSSA) to assess loop diuretic initiation before and after gabapentinoid initiation among older veterans (≥66 years). To identify the cascade, we calculated the adjusted sequence ratio (aSR), which assesses the temporality of LD relative to gabapentinoid initiation. To explore high-risk groups, we used multivariable logistic regression with prescribing order modeled as a binary dependent variable. We calculated adjusted odds ratios (aORs), measuring the extent to which factors are associated with one prescribing order versus another. RESULTS: Of 151,442 veterans who initiated a gabapentinoid, there were 1,981 patients who initiated a LD within 6 months after initiating a gabapentinoid compared to 1,599 patients who initiated a LD within 6 months before initiating a gabapentinoid. In the gabapentinoid-LD group, the mean age was 73 years, 98% were male, 13% were Black, 5% were Hispanic, and 80% were White. Patients in each group were similar across patient and health utilization factors (standardized mean difference <0.10 for all comparisons). The aSR was 1.23 (95% CI: 1.13, 1.34), strongly suggesting the cascade's presence. People age ≥85 years were less likely to have the cascade (compared to 66-74 years; aOR 0.74, 95% CI: 0.56-0.96), and people taking ≥10 medications were more likely to have the cascade (compared to 0-4 drugs; aOR 1.39, 95% CI: 1.07-1.82). CONCLUSIONS: Among older adults, those who are younger and taking many medications may be at higher risk of the gabapentinoid-LD cascade, contributing to worsening polypharmacy and potential drug-related harms. We did not identify strong predictors of this cascade, suggesting that prescribing cascade prevention efforts should be widespread rather than focused on specific subgroups.

Measuring Implicit Bias in ICU Notes Using Word-Embedding Neural Network Models.

BACKGROUND: Language in nonmedical data sets is known to transmit human-like biases when used in natural language processing (NLP) algorithms that can reinforce disparities. It is unclear if NLP algorithms of medical notes could lead to similar transmissions of biases. RESEARCH QUESTION: Can we identify implicit bias in clinical notes, and are biases stable across time and geography? STUDY DESIGN AND METHODS: To determine whether different racial and ethnic descriptors are similar contextually to stigmatizing language in ICU notes and whether these relationships are stable across time and geography, we identified notes on critically ill adults admitted to the University of California, San Francisco (UCSF), from 2012 through 2022 and to Beth Israel Deaconess Hospital (BIDMC) from 2001 through 2012. Because word meaning is derived largely from context, we trained unsupervised word-embedding algorithms to measure the similarity (cosine similarity) quantitatively of the context between a racial or ethnic descriptor (eg, African-American) and a stigmatizing target word (eg, nonco-operative) or group of words (violence, passivity, noncompliance, nonadherence). RESULTS: In UCSF notes, Black descriptors were less likely to be similar contextually to violent words compared with White descriptors. Contrastingly, in BIDMC notes, Black descriptors were more likely to be similar contextually to violent words compared with White descriptors. The UCSF data set also showed that Black descriptors were more similar contextually to passivity and noncompliance words compared with Latinx descriptors. INTERPRETATION: Implicit bias is identifiable in ICU notes. Racial and ethnic group descriptors carry different contextual relationships to stigmatizing words, depending on when and where notes were written. Because NLP models seem able to transmit implicit bias from training data, use of NLP algorithms in clinical prediction could reinforce disparities. Active debiasing strategies may be necessary to achieve algorithmic fairness when using language models in clinical research.

Long-term cognitive outcome after elective hip or knee total joint arthroplasty: A population-based observational study.

BACKGROUND: One year after elective hip or knee total joint arthroplasty (TJA), >30% of older adults meet criteria for postoperative neurocognitive disorder. However, this is not contextualized with long-term cognitive outcomes in comparable surgical and nonsurgical controls. We analyzed population-based data to compare long-term cognitive outcomes in older adults after TJA, other surgeries, and with and without arthritis pain. METHODS: This was a retrospective observational analysis of United States older adults in the Health and Retirement Study (HRS) who underwent elective TJA, or elective surgery without expected functional benefits (e.g., cholecystectomy; inguinal herniorrhaphy), between 1998 and 2018 at aged 65 or older. TJA recipients were also age- and sex-matched to nonsurgical controls who reported moderate-severe arthritic pain or denied pain, so that comparison groups included surgical and nonsurgical (pain-suffering and pain-free) controls. We modeled biennially-assessed memory performance, a measure of direct and proxy cognitive assessments, before and after surgery, normalized to the rate of memory decline ("cognitive aging") in controls to express effect size estimates as excess, or fewer, months of memory decline. We used linear mixed effects models adjusted for preoperative health and demographic factors, including frailty, flexibly capturing time before/after surgery (knots at -4, 0, 8 years; discontinuity at surgery). RESULTS: There were 1947 TJA recipients (average age 74; 63% women; 1358 knee, 589 hip) and 1631 surgical controls (average age 76; 38% women). Memory decline 3 years after TJA was similar to surgical controls (5.2 [95% confidence interval, CI -1.2 to 11.5] months less memory decline in the TJA group, p = 0.11) and nonsurgical controls. At 5 years, TJA recipients experienced 5.0 [95% CI -0.9 to 10.9] months less memory decline than arthritic pain nonsurgical controls. CONCLUSION: There is no systematic accelerated memory decline at 3 years after TJA compared with surgical or nonsurgical controls.

Time to Benefit of Surgery vs Targeted Medical Therapy for Patients With Primary Aldosteronism: A Meta-analysis.

CONTEXT: Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, but the comparative outcomes of targeted treatment remain unclear. OBJECTIVE: To compare the clinical outcomes in patients treated for primary aldosteronism over time. METHODS: Medline and EMBASE were searched. Original studies reporting the incidence of mortality, major adverse cardiovascular outcomes (MACE), progression to chronic kidney disease, or diabetes following adrenalectomy vs medical therapy were selected. Two reviewers independently abstracted data and assessed study quality. Standard meta-analyses were conducted using random-effects models to estimate relative differences. Time to benefit meta-analyses were conducted by fitting Weibull survival curves to estimate absolute risk differences and pooled using random-effects models. RESULTS: 15 541 patients (16 studies) with PA were included. Surgery was consistently associated with an overall lower risk of death (hazard ratio [HR] 0.34, 95% CI 0.22-0.54) and MACE (HR 0.55, 95% CI 0.36-0.84) compared with medical therapy. Surgery was associated with a significantly lower risk of hospitalization for heart failure (HR 0.48 95% CI 0.34-0.70) and progression to chronic kidney disease (HR 0.62 95% CI 0.39-0.98), and nonsignificant reductions in myocardial infarction and stroke. In absolute terms, 200 patients would need to be treated with surgery instead of medical therapy to prevent 1 death after 12.3 (95% CI 3.1-48.7) months. CONCLUSION: Surgery is associated with lower all-cause mortality and MACE than medical therapy for PA. For most patients, the long-term surgical benefits outweigh the short-term perioperative risks.

Development and External Validation of Models to Predict Need for Nursing Home Level of Care in Community-Dwelling Older Adults With Dementia.

Importance: Most older adults living with dementia ultimately need nursing home level of care (NHLOC). Objective: To develop models to predict need for NHLOC among older adults with probable dementia using self-report and proxy reports to aid patients and family with planning and care management. Design, Setting, and Participants: This prognostic study included data from 1998 to 2016 from the Health and Retirement Study (development cohort) and from 2011 to 2019 from the National Health and Aging Trends Study (validation cohort). Participants were community-dwelling adults 65 years and older with probable dementia. Data analysis was conducted between January 2022 and October 2023. Exposures: Candidate predictors included demographics, behavioral/health factors, functional measures, and chronic conditions. Main Outcomes and Measures: The primary outcome was need for NHLOC defined as (1) 3 or more activities of daily living (ADL) dependencies, (2) 2 or more ADL dependencies and presence of wandering/need for supervision, or (3) needing help with eating. A Weibull survival model incorporating interval censoring and competing risk of death was used. Imputation-stable variable selection was used to develop 2 models: one using proxy responses and another using self-responses. Model performance was assessed by discrimination (integrated area under the receiver operating characteristic curve [iAUC]) and calibration (calibration plots). Results: Of 3327 participants with probable dementia in the Health and Retirement Study, the mean (SD) age was 82.4 (7.4) years and 2301 (survey-weighted 70%) were female. At the end of follow-up, 2107 participants (63.3%) were classified as needing NHLOC. Predictors for both final models included age, baseline ADL and instrumental ADL dependencies, and driving status. The proxy model added body mass index and falls history. The self-respondent model added female sex, incontinence, and date recall. Optimism-corrected iAUC after bootstrap internal validation was 0.72 (95% CI, 0.70-0.75) in the proxy model and 0.64 (95% CI, 0.62-0.66) in the self-respondent model. On external validation in the National Health and Aging Trends Study (n = 1712), iAUC in the proxy and self-respondent models was 0.66 (95% CI, 0.61-0.70) and 0.64 (95% CI, 0.62-0.67), respectively. There was excellent calibration across the range of predicted risk. Conclusions and Relevance: This prognostic study showed that relatively simple models using self-report or proxy responses can predict need for NHLOC in community-dwelling older adults with probable dementia with moderate discrimination and excellent calibration. These estimates may help guide discussions with patients and families in future care planning.

Around the EQUATOR with Clin-STAR: Prediction modeling opportunities and challenges in aging research.

The 2015 Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) Statement was published to improve reporting transparency for prediction modeling studies. The objective of this review is to highlight methodologic challenges that aging-focused researchers will encounter when designing and reporting studies involving prediction models for older adults and provide guidance for addressing these challenges. In following the 22-item TRIPOD checklist, researchers must consider the representativeness of cohorts used (e.g., whether older adults with frailty, cognitive impairment, and social isolation were included), strategies for incorporating common geriatric predictors (e.g., age, comorbidities, functional status, and frailty), methods for handling missing data and competing risk of death, and assessment of model performance heterogeneity across important subgroups (e.g., age, sex, race, and ethnicity). We provide guidance to help aging-focused researchers develop, validate, and report models that can inform and improve patient care, which we label "TRIPOD-65."

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis.

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. Exposure: Association between NfL z scores and CDW. Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Frequency of Screening for Colorectal Cancer by Predicted Life Expectancy Among Adults 76-85 Years.

This study assesses whether colorectal cancer screening varied by predicted life expectancy in a national sample of Veterans Affairs patients aged 76 to 85 years.

Association of geriatric measures and global frailty with cognitive decline after allogeneic hematopoietic cell transplantation in older adults.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, and its potential impact on cognition in this population is understudied. This work aims to evaluate the ability of cancer-specific geriatric assessments (cGA) and a global frailty index based on accumulation of deficits identified in the cGA to predict the risk of cognitive decline after alloHCT in older adults. MATERIALS AND METHODS: AlloHCT recipients aged 50 years or older completed a cGA, including a cognitive evaluation by the Blessed Orientation Memory Concentration (BOMC) test, at baseline prior to alloHCT and then at 3, 6, and 12 months after transplant. Baseline frailty was assessed using a deficit accumulation frailty index (DAFI) calculated from the cGA. A multinomial logit model was used to examine the association between predictors (individual cGA measures, DAFI) and the following three outcomes: alive with stable or improved cognition, alive with cognitive decline, and deceased. In post-hoc analyses, analysis of variance was used to compare BOMC scores at baseline, 3, 6, and 12 months across frailty categories. RESULTS: In total, 148 participants were included, with a median age of 62 (range 50-76). At baseline, 12% had cognitive impairment; at one year, 29% of survivors had improved BOMC scores, 33% had stable BOMC, and 37% had worse BOMC. Prior to transplant, 25% were pre-frail and 11% were frail. Individual baseline cGA measures were not associated with cognitive change at one year as assessed by BOMC. Adjusting for age, sex, and education, those who were frail at baseline were 7.4 times as likely to develop cognitive decline at one year than those who were non-frail, although this finding did not reach statistical significance (95% confidence interval [CI] 0.74-73.8, p = 0.09). The probability of being alive with stable/improved cognition at 12 months for the non-frail, pre-frail, and frail groups was 43%, 34%, and 8%, respectively. DISCUSSION: Baseline geriatric measures and frailty were not significantly associated with cognitive change as assessed by BOMC in adults aged 50 or older after alloHCT. However, the study was underpowered to detect clinically meaningful differences, and future work to elucidate potential associations between frailty and cognitive outcomes is warranted.

The association between YouTube use and knowledge of human papillomavirus-related cancers.

Objective: To examine the association between YouTube usage and HPV-related cancer knowledge (cervical, anal, oral and penile). Study design: Cross-sectional study using data from the Health Information National Trends survey conducted between 2017 and 2020 (N = 16,092). Logistic regression was used to analyze the independent effect of YouTube use on cancer knowledge, controlling for sociodemographic characteristics. Results: Respondents' knowledge of HPV-related cancers varied: 49.9% about cervical, 18% anal, 20.1% oral and 20.4% penile cancers. YouTube use was associated with increased knowledge for all cancers (cervical: OR 2.66, 95% CI 2.04, 3.46; anal: OR 1.83, 95% CI 1.32, 2.53; oral: OR 1.89, 95% CI 1.37, 2.61; penile OR 2.00, 95% CI 1.44, 2.77) in models adjusted for all covariates. Other independent predictors of HPV-related cancer knowledge included female gender, younger age, a higher income, and higher education. Conclusions: YouTube could play an important role in educating people about HPV-related cancers and should also target other populations, such as males and those with less formal education. Innovation: The study provides novel insights into the potential of YouTube as an educational tool for promoting cancer knowledge with the goal of cancer prevention.

Medication misuse and overuse in community-dwelling persons with dementia.

BACKGROUND: Persons with dementia (PWD) have high rates of polypharmacy. While previous studies have examined specific types of problematic medication use in PWD, we sought to characterize a broad spectrum of medication misuse and overuse among community-dwelling PWD. METHODS: We included community-dwelling adults aged ≥66 in the Health and Retirement Study from 2008 to 2018 linked to Medicare and classified as having dementia using a validated algorithm. Medication usage was ascertained over the 1-year prior to an HRS interview date. Potentially problematic medications were identified by: (1) medication overuse including over-aggressive treatment of diabetes/hypertension (e.g., insulin/sulfonylurea with hemoglobin A1c < 7.5%) and medications inappropriate near end of life based on STOPPFrail and (2) medication misuse including medications that negatively affect cognition and medications from 2019 Beers and STOPP Version 2 criteria. To contextualize, we compared medication use to people without dementia through a propensity-matched cohort by age, sex, comorbidities, and interview year. We applied survey weights to make our results nationally representative. RESULTS: Among 1441 PWD, median age was 84 (interquartile range = 78-89), 67% female, and 14% Black. Overall, 73% of PWD were prescribed ≥1 potentially problematic medication with a mean of 2.09 per individual in the prior year. This was notable across several domains, including 41% prescribed ≥1 medication that negatively affects cognition. Frequently problematic medications included proton pump inhibitors (PPIs), non-steroidal anti-inflammatory drugs (NSAIDs), opioids, antihypertensives, and antidiabetic agents. Problematic medication use was higher among PWD compared to those without dementia with 73% versus 67% prescribed ≥1 problematic medication (p = 0.002) and mean of 2.09 versus 1.62 (p < 0.001), respectively. CONCLUSION: Community-dwelling PWD frequently receive problematic medications across multiple domains and at higher frequencies compared to those without dementia. Deprescribing efforts for PWD should focus not only on potentially harmful central nervous system-active medications but also on other classes such as PPIs and NSAIDs.

Effect of the COVID-19 pandemic on meaningful activity engagement in racially and ethnically diverse older adults.

BACKGROUND: Participation and active engagement in meaningful activities support the emotional and physical well-being of older adults. In 2020, the onset of the COVID-19 pandemic altered lives, including the ability to participate in meaningful activities. This study compared meaningful activity engagement before and at the beginning of the COVID-19 pandemic in a nationally representative, diverse sample >65 years between 2015 and 2020. METHODS: We described the proportions and characteristics of National Health and Aging Trends Study participants and their engagement in four activities: visiting friends or family, attending religious services, participating in clubs/classes/other organized activities, and going out for enjoyment. We used mixed effects logistic regressions to compare probabilities of activity engagement before 2020 and in 2020, adjusting for age, sex, functional status, income, geographic region, anxiety-depression, and transportation issues. RESULTS: Of 6815 participants in 2015, the mean age was 77.7 (7.6) years; 57% of participants were female; 22% were Black, 5% Hispanic, 2% were American Indian, and 1% were Asian; 20% had disability; and median income was $33,000. Participation in all four activities remained consistent between 2015 and 2019 and declined in 2020. Significant differences existed in attending religious services (p < 0.01) and going out for enjoyment (p < 0.001) by race and ethnicity, before and after the start of COVID-19. Black and Hispanic participants experienced the largest decline in attending religious services (-32%, -28%) while Asian and White participants experienced the largest decline in going out for enjoyment (-49%, -56%). CONCLUSIONS: Potential quality of life tradeoffs should be considered to a greater extent in future pandemic emergencies.

Trends in the Use of Gabapentinoids and Opioids in the Postoperative Period Among Older Adults.

Importance: In response to the opioid epidemic, recommendations from some pain societies have encouraged surgeons to embrace multimodal pain regimens with the intent of reducing opioid use in the postoperative period, including by prescribing gabapentinoids. Objective: To describe trends in postoperative prescribing of both gabapentinoids and opioids after a variety of surgical procedures by examining nationally representative Medicare data and further understand variation by procedure. Design, Setting, and Participants: This serial cross-sectional study of gabapentinoid prescribing from January 1, 2013, through December 31, 2018, used a 20% US Medicare sample. Gabapentinoid-naive patients 66 years or older undergoing 1 of 14 common noncataract surgical procedures performed in older adults were included. Data were analyzed from April 2022 to April 2023. Exposure: One of 14 common surgical procedures in older adults. Main Outcomes and Measures: Rate of postoperative prescribing of gabapentinoids and opioids, defined as a prescription filled between 7 days before the procedure and 7 days after discharge from surgery. Additionally, concomitant prescribing of gabapentinoids and opioids in the postoperative period was assessed. Results: The total study cohort included 494 922 patients with a mean (SD) age of 73.7 (5.9) years, 53.9% of whom were women and 86.0% of whom were White. A total of 18 095 patients (3.7%) received a new gabapentinoid prescription in the postoperative period. Of those receiving a new gabapentinoid prescription, 10 956 (60.5%) were women and 15 529 (85.8%) were White. After adjusting for age, sex, race and ethnicity, and procedure type in each year, the rate of new postoperative gabapentinoid prescribing increased from 2.3% (95% CI, 2.2%-2.4%) in 2014 to 5.2% (95% CI, 5.0%-5.4%) in 2018 (P < .001). While there was variation between procedure types, almost all procedures saw an increase in both gabapentinoid and opioid prescribing. In this same period, opioid prescribing increased from 56% (95% CI, 55%-56%) to 59% (95% CI, 58%-60%) (P < .001). Concomitant prescribing also increased from 1.6% (95% CI, 1.5%-1.7%) in 2014 to 4.1% (95% CI, 4.0%-4.3%) in 2018 (P < .001). Conclusions and Relevance: The findings of this cross-sectional study of Medicare beneficiaries suggest that new postoperative gabapentinoid prescribing increased without a subsequent downward trend in the proportion of patients receiving postoperative opioids and a near tripling of concurrent prescribing. Closer attention needs to be paid to postoperative prescribing for older adults, especially when using multiple types of medications, which can have adverse drug events.

MWF of the corpus callosum is a robust measure of remyelination: Results from the ReBUILD trial.

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

Clinical Outcomes of Intensive Inpatient Blood Pressure Management in Hospitalized Older Adults.

Importance: Asymptomatic blood pressure (BP) elevations are common in hospitalized older adults, and widespread heterogeneity in the clinical management of elevated inpatient BPs exists. Objective: To examine the association of intensive treatment of elevated inpatient BPs with in-hospital clinical outcomes of older adults hospitalized for noncardiac conditions. Design, Setting, and Participants: This retrospective cohort study examined Veterans Health Administration data between October 1, 2015, and December 31, 2017, for patients aged 65 years or older hospitalized for noncardiovascular diagnoses and who experienced elevated BPs in the first 48 hours of hospitalization. Interventions: Intensive BP treatment following the first 48 hours of hospitalization, defined as receipt of intravenous antihypertensives or oral classes not used prior to admission. Main Outcome and Measures: The primary outcome was a composite of inpatient mortality, intensive care unit transfer, stroke, acute kidney injury, B-type natriuretic peptide elevation, and troponin elevation. Data were analyzed between October 1, 2021, and January 10, 2023, with propensity score overlap weighting used to adjust for confounding between those who did and did not receive early intensive treatment. Results: Among 66 140 included patients (mean [SD] age, 74.4 [8.1] years; 97.5% male and 2.6% female; 17.4% Black, 1.7% Hispanic, and 75.9% White), 14 084 (21.3%) received intensive BP treatment in the first 48 hours of hospitalization. Patients who received early intensive treatment vs those who did not continued to receive a greater number of additional antihypertensives during the remainder of their hospitalization (mean additional doses, 6.1 [95% CI, 5.8-6.4] vs 1.6 [95% CI, 1.5-1.8], respectively). Intensive treatment was associated with a greater risk of the primary composite outcome (1220 [8.7%] vs 3570 [6.9%]; weighted odds ratio [OR], 1.28; 95% CI, 1.18-1.39), with the highest risk among patients receiving intravenous antihypertensives (weighted OR, 1.90; 95% CI, 1.65-2.19). Intensively treated patients were more likely to experience each component of the composite outcome except for stroke and mortality. Findings were consistent across subgroups stratified by age, frailty, preadmission BP, early hospitalization BP, and cardiovascular disease history. Conclusions and Relevance: The study's findings indicate that among hospitalized older adults with elevated BPs, intensive pharmacologic antihypertensive treatment was associated with a greater risk of adverse events. These findings do not support the treatment of elevated inpatient BPs without evidence of end organ damage, and they highlight the need for randomized clinical trials of inpatient BP treatment targets.

Comparative mRNA booster effectiveness against death or hospitalization with COVID-19 pneumonia across at-risk US Veteran populations.

Studies of comparative mRNA booster effectiveness among high-risk populations can inform mRNA booster-specific guidelines. The study emulated a target trial of COVID-19 vaccinated U.S. Veterans who received three doses of either mRNA-1273 or BNT162b2 vaccines. Participants were followed for up to 32 weeks between July 1, 2021 to May 30, 2022. Non-overlapping populations were average and high risk; high-risk sub-groups were age ≥65 years, high-risk co-morbid conditions, and immunocompromising conditions. Of 1,703,189 participants, 10.9 per 10,000 persons died or were hospitalized with COVID-19 pneumonia over 32 weeks (95% CI: 10.2, 11.8). Although relative risks of death or hospitalization with COVID-19 pneumonia were similar across at-risk groups, absolute risk varied when comparing three doses of BNT162b2 with mRNA-1273 (BNT162b2 minus mRNA-1273) between average-risk and high-risk populations, confirmed by the presence of additive interaction. The risk difference of death or hospitalization with COVID-19 pneumonia for high-risk populations was 2.2 (0.9, 3.6). Effects were not modified by predominant viral variant. In this work, the risk of death or hospitalization with COVID-19 pneumonia over 32 weeks was lower among high-risk populations who received three doses of mRNA-1273 vaccine instead of BNT162b2 vaccine; no difference was found among the average-risk population and age >65 sub-group.